The extent of the communication between the nervous, endocrine, and immune system is just beginning to be realized and serves as the focus of this program. Investigation into the ultimate health outcomes of stressful events have, for the most part, focused on infectious disease or cancer endpoints both in humans and in animals. In this application, we propose to investigate the effect of stress on the outcome of an experimental autoimmune disease, experimental allergic encephalomyelitis (EAE). This model, extremely well characterized clinically, histopathologically and immunologically in the rat, is a T cell-mediated autoimmune response to myelin protein (MBP). Initial experiments will focus on defining the effect of stress (restraint, cold water swimming, administration of exogenous neuro- endocrine hormones) on the course of EAE in the rat, as defined by a change in EAE clinical signs, CNS histopathologic changes, or immunologic responses to MBP. Second, specific effects of stress on T cell immune parameters will be measured, viz., delayed hypersensitivity, lymphokine secretion and antigen-specific proliferative responses. Moreover, the effects of stress and stress-related hormones on the activity of MBP-specific T cells lines will be assessed. Third, the contribution of neuro-endocrine hormones to the natural course of EAE, i.e., rapid onset of clinical signs and rapid spontaneous recovery will be determined by measuring corticosterone, ACTH, epinephrine, met-enkephalin, and beta-endorphin throughout the course of disease. Fourth, the effect of stress on gastrointestinal immune response will also be assessed utilizing an MBP-induced oral tolerance model. Since regulating tolerance to dietary antigens, MBP-specific immune responses will be assessed concomitantly with gut hormones following oral administration of MBP.